Bio-based Green Solvents in Organic Synthesis. An Updated Review

Abstract

Solvents are essential for chemical reactions, formulations, and purification, with major use in paints, coatings, and pharmaceuticals. Global demand for solvents is expected to exceed 32 million metric tons by 2026. Solvents facilitate reactions, stabilize catalysts, assist in purification steps, and aid in the stability of reaction intermediates and transition states, which are crucial to the success of the chemical reaction. However, most of the solvents are petroleum-based, toxic, and environmentally harmful. The growing use of industrial solvents exacerbates the problems of waste and pollution. Therefore, there is an urgent need for alternative and sustainable solvents to replace current fossil-based ones. Green chemistry principles advocate for safer, renewable solvents to reduce environmental and health risks. The Sustainable Development Goals (SDGs) further emphasize clean water, innovation, and climate action. In this sense, bio-based solvents derived from renewable biomass feedstock are a promising alternative to petroleum-based solvents. While ethanol is widely used, newer options like carbohydrate-based solvents, terpenes, and natural deep eutectic solvents (NaDESs) are gaining attention. Other solvents, such as vegetable and animal oils and their derivatives, will not be discussed here, given that their benefits are limited and also that there is a scarcity of relevant literature. This review explores advancements made with regard to bio-based solvents over the past 5 years (from 2019 to the present). Over 70 studies are presented in this review regarding the use of bio-based solvents, highlighting their potential to replace conventional fossil-based ones, such as dichloromethane and toluene.

 

MissingLinkText

Keywords

Bio-based solvents - Green chemistry - Biomass - Organic synthesis

Significance

Solvents are vital for chemicals, paints, and pharma, with demand that will surpass 32 M tons by 2026. Most solvents are toxic, petroleum-based, and polluting. Green chemistry and SDGs push for sustainable alternatives like bio-based solvents (e.g., ethanol, terpenes, and NaDES). This review covers advancements made in renewable solvents obtained from carbohydrates, terpenes, and NaDES during the period from 2019 to 2024, analyzing 70+ studies for eco-friendly replacements.

1

Introduction

Solvents are often present as the main component of chemical reactions, formulations, and purification steps. They are also present in a wide range of applications, with the paint and coating industry contributing the most to their use,[1] followed by the pharmaceutical industry. It is estimated that the global demand for solvents will exceed 32 million metric tons by 2026 ([Fig. 1]).[2]

Fig. 1 The necessary transition from fossil- to bio-based solvents.[1]

Regarding chemical transformations and processes, solvents play a crucial role in providing a medium for intermolecular interactions, dissipating thermal energy, and stabilizing and governing the activity of catalysts and biocatalysts/enzymes. They also play an important role in the stability of intermediates and transition states.[3] Despite these advantages, much is required for their separation, extraction, and purification processes.[4]

The pharmaceutical and fine chemicals industries are two of the four key sectors of the chemical industry, together with the paint and coating industries, that produce coproducts and waste. The pharmaceutical industries also require a variety of organic solvents to synthesize and purify intermediates at different reaction steps until the final active ingredient is obtained.

Most classic organic solvents commonly used in industry and research laboratories are nonrenewable, oil-based ones and are associated with high toxicity and hazardousness. Furthermore, the continuous growth of industrial processes has resulted in an ever-increasing demand for solvents and a corresponding increase in waste generation.

However, it is common knowledge and a matter of public concern that there is an urgent need to reduce the use of chemical substances that involve environmentally damaging manufacturing processes and also when their uses are characterized as hazardous to health and the environment. The concept of green chemistry, guided by the 12 green chemistry principles, has helped to shape new organic chemistry practices, driving researchers to search for alternative approaches to classic chemical reactions.[5] Less hazardous chemical synthesis (principle #3), safer solvents and auxiliaries (principle #5), use of renewable feedstocks (principle #7), and design for degradation (principle #10) are those principles that encourage rethinking on how to design and use environmentally benign, biodegradable, and sustainable solvents.

At the same time, the agenda of the Sustainable Development Goals (SDGs) aims to reduce the human impact on a more sustainable world.[6] In this context, the use of green solvents directly impacts clean water and sanitation (Goal #6); industry, innovation, and infrastructure (Goal #9); and climate action (Goal #13).

Water and water-based solvent systems also contribute largely to sustainable reaction protocols. This fascinating reaction system has aroused the interest of organic chemists since the last decades of the last century.[7] New concepts, such as in-water and on-water reactions were coined, demonstrating the advantages and limitations of this approach.[8] However, the large-scale use of water in chemical industry processes also raises a number of concerns. One of these is the contamination of a fundamental resource for life on the planet. As emphasized by Blackmond et al., “Water is only a truly green solvent if it can be directly discharged to a biological effluent treatment plant.”[9]

Solvent-reducing or solvent-free approaches have increased over the years, supported by the so-called enabling technologies, such as microwave irradiation, sonochemistry, flow chemistry, and mechanochemistry.[10] However, the complete elimination of solvent-mediated processes may not be feasible for all classes of reactions and substrates.[9]

In this case, the use of alternative solvents that promote a reaction with the same or similar efficiency as the classical ones but with less damage to the environment is highly desirable. In addition, solvent waste minimization through solvent recovery, recycling, and reuse, as well as safe disposal, are actions that should be widely disseminated and practiced in industry and academia.

Several book chapters and reviews have addressed the perspectives and examples of using “green solvents” in organic reactions. Green solvents include water,[11] ionic liquids,[12] supercritical carbon dioxide,[13] deep eutectic,[14] fluorous solvents,[15] and liquid polymers such as polyethylene glycol (PEG).[16] Except for water and carbon dioxide, the above-mentioned green solvents are mostly oil-based ones.[17]

The field of biomass-based solvents has the potential to replace traditional oil-based solvents and fulfill most of the requirements of a green solvent, including sustainability, since these solvents are obtained from renewable feedstocks.[18] Although bio-based solvents are not yet widely available, with the exception of ethanol, obtained from the fermentation of biomass (mainly corn and sugar cane), researchers in this field are seeking to understand how these solvents promote relevant organic reactions and how they are suitable for phasing out oil-based solvents.

This review discusses bio-based solvents and recent research efforts aimed at using them in organic reactions. Some classes of bio-based solvents have recently been described in the literature.[19] Here, we will discuss some recent examples of the uses of new bio-based solvents that have not been reviewed in articles to date. This will provide a broader view of the use of these new solvents in organic synthesis.

Ethanol is not included among the solvents covered by this review. Although ethanol is certainly the most widely used bio-based solvent, it is not considered an unconventional, new-generation green solvent. This is mostly because oil-based ethanol (obtained from the hydration of ethylene) has been used for years in the chemical industry.[20] Glycerol, except when present as a component of a deep eutectic mixture, is also not covered in this review, as its use as a solvent has recently been described in excellent review articles and book chapters.[21] Thus, after excluding solvents such as glycerol and ethanol, the search was carried out on other bio-based solvents used in organic synthesis since 2019. The selected articles were procured from databases such as “Web of Science” and “Science Direct” using keywords such as “bio-based solvents,” the specific name of the solvents, “organic synthesis,” and “chemical reactions.” Following this step, we excluded those articles where these new solvents are used in procedures such as extraction or purification. Thus, in this review, more than 70 articles are considered, and they comprise three sections based on the biomass source of the solvent: (1) carbohydrate-based solvents; (2) terpene-based solvents; and (3) NaDES as the reaction medium ([Scheme 1]).

Scheme 1 Bio-based solvents and products accessed.

 

MissingLinkText

2

Carbohydrate-Based Solvents

This section discusses the reactions conducted in the presence of solvents derived from carbohydrates obtained from renewable resources, mostly cellulose and lignocellulose. These solvents have been explored as a promising alternative to conventional organic solvents.[22] Besides being less toxic, these solvents represent a solution for agricultural residues, lignocellulosic biomass, and other cellulose waste, providing a wide range of chemical products and adding value to materials that would otherwise be decomposed or burned for disposal.[23] Furthermore, these solvents often have low volatility and present both high biodegradability, low toxicity, and mutagenicity compared to petroleum-derived organic solvents, and in this way, they represent a valid alternative.[22] [23]

For instance, cyrene and γ-valerolactone (GVL) are dipolar aprotic solvents obtained from renewable sources. Cyrene is derived from cellulose, and GVL is produced from levulinic acid present in lignocellulosic biomass. In addition to these two alternative solvents, 2-methyltetrahydrofuran (2-MeTHF) presents similar characteristics, and it can be obtained from furfural. Similarly, dimethyl isosorbide (DMI) can be synthesized from cellulose via the glucose and sorbitol route ([Scheme 2]).[22] In this section, we describe the use of these solvents in important organic transformations through different organic synthesis protocols.

Scheme 2 Synthesis of γ-valerolactone (GVL), cyrene, 2-methyltetrahydrofuran, and dimethyl isosorbide (DMI).

2.1

Cyrene

In 2019, Camp and coworkers[24] used cyrene as a solvent for the synthesis of amides 3 from acid chlorides 1 and primary aliphatic and secondary amines 2. The authors studied three different work-up procedures: (a) an aqueous work-up followed by column chromatography; (b) only column chromatography; and (c) a direct precipitation. The results proved that the work-up procedure eliminated the need to use petroleum-based solvents, such as halogenated solvents or dimethylformamide (DMF), which are commonly used as the mainstay of industrial synthesis. The simple addition of water allowed the complete removal of cyrene, and this caused the product to precipitate. Moreover, to compare this method with conventional ones reported in the literature, an Excel-based Mol. E% calculator was developed. The calculations showed that the cyrene precipitation method was significantly more efficient than the previously related protocols, which used more toxic solvents, such as DMF and dichloromethane. However, it was observed that amides derived from primary aliphatic or benzylic amines could be directly precipitated from cyrene, while secondary amine reaction products required purification by column chromatography. Moreover, seventeen desired products 3 were synthesized, bearing electron-withdrawing and -donating groups and cyclic, heterocyclic, and aliphatic substituents in 32–91% yield. Additionally, a gram-scale reaction (5 mmol) was studied, and the desired product 3a was achieved in 77% yield ([Scheme 3]).

Scheme 3 Cyrene as a solvent in the synthesis of amides 3.

In [Scheme 4], Lee and colleagues[25] reported a multicomponent reaction of amines 2, chromones 4, and acetonitriles 5 using cyrene as a solvent to give polysubstituted bipyridine derivatives or aryl pyridines 6. A total of thirty-nine examples of bipyridine or aryl pyridines 6 were obtained in 62–96% yield, after irradiating the reaction mixture with microwaves for 1 h. When anilines ortho-, meta-, and para-substituted with electron-activating or electron-deactivating groups were used, the desired products were furnished in 86–96% yield. Also, aliphatic and cyclic amines were investigated, and the corresponding products were obtained in 62–96% yield. Additionally, reactions of different 3-formylchromones were carried out, and products containing electron-donating, electron-withdrawing, and electron-poor groups were obtained in 77–96% yield. Moreover, the scope was extended to include cyano-compounds bearing aryl groups, and the products were formed in excellent yields. Unfortunately, the reactions with benzyl cyanide and 4-methylbenzyl cyanide were not successful, and the desired products were not obtained. Furthermore, compounds 6a and 6b, synthesized by this methodology, proved to be good candidates for applications in pollution monitoring, catalysis, and functional materials, once they are detectors of heavy metals, such as mercury(II), copper(II), and iron(III) ions. The authors highlight that water was the only by-product in the reaction, and the solvent can be recovered and recycled.

Scheme 4 Microwave-promoted synthesis of aryl pyridines 6.

In 2023, Arnold and coworkers[26] employed a mixture of cyrene and GVL (1:1) as solvent in the reductive homocoupling of pyridine 7 to obtain bipyridine 8, in the presence of palladium acetate (15 mol%), tetrabutylammonium iodide (TBAI, 1.2 equiv), potassium carbonate (1.6 equiv), and isopropanol (2.2 equiv) at 50 °C ([Scheme 5]). Through this procedure, nine examples were synthesized, and all conversions were calculated using high-performance liquid chromatography (HPLC) (6.3–100%). The authors employed the DOZN™ quantitative scoring analysis to assess the 12 principles of green chemistry for the optimized process using GVL/cyrene and compared it with the reaction with DMF, the solvent commonly used. The analysis demonstrated score differences in the use of less hazardous materials, design of safer chemicals, and safer solvents and auxiliaries. All analyses revealed good results; in other words, lower values than those of the reaction conducted in DMF. Finally, they established that the solvent blend significantly reduced the reaction time compared to the reaction conducted using DMF, from 6 to 1 h.

Scheme 5 Synthesis of bipyridine 8 using cyrene/GVL as solvent.

In the same year, a palladium-catalyzed Mizoroki–Heck cross-coupling reaction was described using a wide range of substituted aryl iodides 9 (1 mmol), acrylates 10, styrene 11a, or acrylamides 12 (1.2 mmol), in the presence of triethylamine (0.75 equiv) as base, Pd/C as catalyst, in cyrene as solvent, and at 150 °C for 1 h ([Scheme 6]).[27] Noteworthy, the study was also performed using potassium carbonate as a base instead of triethylamine, which provided similar results but was avoided by the authors because it favored aldol condensation, thus preventing solvent reuse. Several aryl iodides containing electron-withdrawing and -donating groups were employed, affording the corresponding products 13–15 in excellent yields. In addition, the recyclability of the solvent was tested by applying the protocol on an industrial scale, and it was possible to reuse cyrene for up to four consecutive cycles, requiring only thermal treatment of the water. For gram-scale applications, it was necessary to change the purification method, replacing column chromatography with a second extraction, achieving the desired product in 91% yield.

Scheme 6 Mizoroki–Heck cross-coupling reaction using cyrene as a solvent.

Citarella, Fasano, and coworkers[28] reported in 2024 the synthesis of nicotinic ester derivatives 19 through the nucleophilic aromatic substitution reaction between chloro-substituted nicotinic esters 16 (1 mmol) and phenols 17 or thiophenols 18 (1.1 mmol) ([Scheme 7]). Firstly, the authors investigated K₂CO₃ as a base, but cyrene polymerization was observed. This problem was circumvented by using Et₃N instead of K₂CO₃. The optimal reaction condition was encountered when using 2 mmol of Et₃N as base, 0.3 mL of cyrene as solvent, at 150 °C temperature. Under the optimal conditions, twenty-four functionalized nicotinic esters 19 were obtained in 60–91% yield after only 15 min of reaction. Different substituents containing electron-withdrawing and electron-donating groups were used, and all were well tolerated by the method.

Scheme 7 Synthesis of functionalized nicotinic esters 19 using cyrene as a solvent.

 

MissingLinkText

2.2

γ-Valerolactone

In 2019, Ackermann and coworkers[29] reported the first electrochemical cobalt-catalyzed C–H acyloxylation of different amides 3 with carboxylic acids 20. The best reaction condition was found when the authors used amides 3 (0.25 mmol), carboxylic acids 20 (2 equiv), cobalt(II) salts (20 mol%), and Na₂CO₃ as base (2 equiv), in an undivided cell with an anode made of reticulated vitreous carbon (RVC), and a Pt-plate cathode setup at 80 °C at constant current electrolysis (CCE) at 5 mA in γ-valerolactone (GVL) as solvent for 6 h. The versatility of this method was explored with various substituted aromatic benzamides, and it was possible to obtain six different esters 21 in 51–66% yield ([Scheme 8]). The authors also tested different carboxylic acids bearing ortho-, meta-, and para-substituents, electron-rich and electron-deficient, and all of them were well tolerated, giving seven examples in 38–64% yield. In addition, acetic acid was used, giving the expected product 21a in 32% yield.

Scheme 8 Electrochemical C–H acyloxylation of amides in GVL.

In the same year, Jensen and colleagues[30] described, for the first time, the use of GVL as a solvent for decarbonylative dehydration of fatty acid derivatives. The optimal reaction condition was found using stearic acids 20 (1 mmol), precatalyst Pd(cinnamyl)Cl(DPEPhos) (1 mol%) with bis[(2-diphenylphosphino)phenyl] ether (DPEphos) used as precatalyst ligand, Piv₂O (2 equiv), pyridine (9 mol%), in GVL as solvent at 110 °C for 15 h. A total of nine different linear α-olefins 22 were obtained, whose yields were calculated by nuclear magnetic resonance (NMR) ([Scheme 9]). One of the challenges of this protocol was the use of a stoichiometric amount of pivalic anhydride (Piv₂O) to activate the fatty acid substrate. After environmental factor calculations (E-factor), which estimated the amount of waste generated in the chemical reaction, the authors reported that using the activator together with other coproducts provided an E-factor value higher than expected.

Scheme 9 Synthesis of linear α-olefins 22 in GVL.

In 2020, Cravotto and coworkers[31] reported an MW-assisted protocol for the C–H arylation of thiophenes 23 with substituted aryl halide 9 in GVL as solvent, catalyzed by Pd nanoparticles embedded in cross-linked β-cyclodextrin (Pd/CβCAT) ([Scheme 10]). The optimal reaction condition involved aryl halides 9 (0.5 mmol), thiophenes 23 (2 equiv), KOAc (2 equiv), and PivOH (0.15 mmol) in GVL as solvent. The heterogeneous catalyst (Pd/CβCAT; 0.2 mol%) and the previous mixture were heated at 140 °C under microwave (MW) irradiation for 2 h under an N₂ atmosphere, affording the desired products 24 in 3–99% yield. The optimized condition was applied to other substituted thiophenes and halides, and the activity of two catalysts (Pd(OAc)₂ and Pd/CβCAT) was compared. The activity of Pd/CβCAT was compared with that of another homogeneous catalyst used in a previous work by the same authors.[32] It was observed that MW improved the reaction performance when compared to the same reaction under conventional heating. The procedure using heterogeneous catalysis generated eighteen examples, while nineteen examples were obtained using homogeneous catalysis. The 4(3H)-quinazolinone derivative was prepared by a one-pot approach. A pressure MW reactor with multiple gas inlets was used for C–H arylation, reduction, and carbonylation, sequentially, in the presence of the same catalyst (Pd/CβCAT), but under different gas atmospheres. After washing the catalyst with water, methanol, and acetone, it was reused in the synthesis of 24a (R = Me), which was obtained in 90% yield.

Scheme 10 C–H arylation of thiophenes 23 in GVL.

In the same year, Mika and colleagues[33] described the synthesis of esters 25 by the alkoxy- and aryloxycarbonylation reaction employing a phosphine-free Pd-catalyst system and GVL as a biomass-based solvent ([Scheme 11]). The authors encountered the best reaction condition by applying aryl iodides 9 (0.5 mmol), phenols 17 (1.25 equiv), Pd(OAc)₂ (0.25 mol%), and K₂CO₃ (2.5 equiv) as base in the presence of 2.5 mL of GVL, in 7 bar of CO, at 100 °C for 3 h. Under these reaction conditions, twenty-five aryl esters 25 were obtained in 39–99% yield. Initially, the authors applied different aryl iodides containing electron-donating and electron-withdrawing groups, giving fifteen different products in 39–99% yield. Apparently, substituents containing electron-withdrawing groups, such as p-Cl and p-Br attached to the aryl iodides, were more reactive, giving the products 25a and 25b in 99% yield. However, the electron-donating t-butyl group caused a significant decrease in the yield, and the product 25c was prepared in only 39%. Furthermore, substituted phenolic substrates were tested and ten products were achieved in 50–91% yield ([Scheme 11], Eq. A). Finally, the protocol was extended to the alkoxycarbonylation with alcohols 26, using Et₃N or K₂CO₃ as base. The respective alkyl esters were obtained in 13–99% yield ([Scheme 11], Eq. B).

Scheme 11 Different approaches to prepare aryl esters in GVL.

In 2023, the same research group[34] published a kinetic and mechanistic study of the selective hydrogenation of carbon–carbon double bond of (E)-chalcones (CHLs) in GVL as solvent and triphenylphosphine-modified rhodium as catalyst. The optimal reaction condition was found using chalcones 27 (10 mmol), the catalyst precursor rhodium bis((1,2,5,6-eta)-1,5-cyclooctadiene)-tetrafluoroborate, [Rh(cod)₂]⁺[BF₄]⁻ (0.004 mmol), and PPh₃ (0.012 mmol) in GVL under argon atmosphere ([Scheme 12]). The reactor for hydrogenation was pressurized at 50 bar with hydrogen and heated at 60 °C for 5 h. This protocol allowed the hydrogenation of various derivatives of CHL, with different substituents on the styryl phenyl groups. A total of nine dehydrogenated chalcones 28 were selectively prepared for the hydrogenation of the C=C double bond, giving 100% conversion in all cases. Furthermore, kinetic studies and NMR spectra evaluations were conducted by using the cationic Rh–PPh₃ system, showing that the olefin insertion was the rate-determining step.

Scheme 12 Synthesis of dehydrogenated chalcones 28 in GVL.

In 2022, Zhang and coworkers[35] described the rhodium-catalyzed addition reaction of aldehydes 29 with arylboronic acids 30 in aqueous GVL to form the corresponding alcohols 26 ([Scheme 13]). The best reaction conditions were determined using 4-nitrobenzaldehyde 29a (0.2 mmol) and arylboronic acid 30 (1.5 equiv), in the presence of Rh(PPh₃)₃Cl (0.5 mol%) as catalyst, Na₂CO₃ (1.5 equiv) as base, and a mixture GVL/H₂O (1:1) as solvent, under N₂ atmosphere at 110 °C for 6 h. A total of seventeen alcohols 26 were obtained in moderate to good yields by fixing 29a (R = 4-NO₂C₆H₄) and varying the arylboronic acid 30. Additionally, the authors used eighteen differently substituted aldehydes, alkyl derivatives included (R = CH₂C₆H₅, ⁿ C₅H_11, ^t C₄H₉), in the reaction with phenylboronic acid 30a (Ar = C₆H₅). In this case, however, both the amount of Rh(PPh₃)₃Cl and time were increased, to 1 mol% and 12 h, respectively.

Scheme 13 Synthesis of aryl alcohols in GVL/H₂O.

In 2020, De Vos, Vaccaro, and coworkers[36] developed a selective procedure for the direct C2-arylation of indoles 31 using a Pd-loaded metal-organic framework (MOF) as a heterogeneous catalyst and GVL as solvent. The optimal condition involved stirring a mixture of the indole 31 (1 mmol), diaryliodonium tetrafluoroborate salt 32 (1.2 equiv) as arylating agent, and Pd-loaded UiO-66-BTeC as heterogeneous catalyst (1 mol%) at 80 °C for 5 h in GVL ([Scheme 14]). Twelve 2-substituted indoles 33 were obtained in 26–94% yield, presenting excellent selectivity for arylation at the C2 position. There is no clear electronic effect caused by substituents in the phenyl ring of the indole counterpart 31. However, the presence of a strong electron-donor group at the para-position of the iodonium salt 32 (R³ = OMe) or of a substituent at the 3-position of 31 negatively affected the reaction, reducing the yield (like in 33c and 33i) or even preventing the arylation of the indole, as in 33d and 33e. After the first cycle, the catalytic system was recovered and reused for a second and a third reaction.

Scheme 14 Synthesis of 3-arylindoles 33 in GVL.

In the following year, the same group[37] reported the synthesis of N-methoxybenzamides 35 and anilide derivatives 37 through the Fujiwara–Moritani C–H alkenylation reaction employing GVL as solvent and heterogeneous palladium as catalyst ([Scheme 15]). The reaction was carried out by stirring a mixture of 0.3 mmol of acetanilide 34 or anilide 36, acrylate 10 (1.5 equiv), p-toluenesulfonic acid immobilized on polystyrene, 1 equiv (PS-TsOH), p-benzoquinone (BQ, 20 mol%), and Pd/C (10 mol% for 34; 7.5 mol% for 36) as catalyst in GVL (0.05 M) at 60 °C or 120 °C under an oxygen atmosphere, for 24 h ([Scheme 15], Eq. A). By this approach, a total of nine 2-methoxyisoindolin-1-ones 35 (120 °C, 7–85% yield) and eleven ortho-alkenyl anilides 37 (60 °C, 20–75% yield) were obtained. The authors emphasized that the use of GVL as a solvent allowed the recovery and recycling of the catalytic system for at least three consecutive reactions.

Scheme 15 Fujiwara–Moritani C–H alkenylation in GVL.

In the same year, Vaccaro’s group[38] reported a flow version of the same reaction using a tube-in-tube flow reactor and GVL as solvent for the preparation of substituted N-methoxybenzamides 35 and acetanilides 37 ([Scheme 16]). In this case, the reaction scope was extended to other alkenes 10, like acrylonitrile and styrene. The optimal reaction conditions were achieved when acetanilide 34 or 36 (2.5 mmol) and alkenes 10 (1.5 equiv) were reacted in the presence of benzoquinone (10 mol%), p-toluenesulfonic acid (1 equiv), and Pd/C (0.056 mmol) as a heterogeneous catalyst in GVL. The reaction mixture flowed in an oxygen tube-in-tube flow system with a flow rate of 10 μL min⁻¹ and a 150 cm reactor length. Through this methodology, five N-methoxybenzamides 35 (80–90% yield) and eleven substituted acetanilides 37 (75–93% yield) were obtained. Furthermore, the authors calculated the E-factor and obtained a result of 3.0 (i.e., 3.0 kg of waste for each kg of product), which was considered suitable for this reaction, compared to previously described works. Additional green metrics, such as reaction mass efficiency (RME) and material recovery parameter (MRP), were calculated to demonstrate the sustainability of the newly developed flow protocol.

Scheme 16 Flow synthesis of N-methoxybenzamides 35 and acetanilides 37 in GVL.

In 2024, the same group[39] developed a microwave-assisted Suzuki–Miyaura cross-coupling reaction using GVL as a green solvent and Pd/PiNe (palladium supported at waste-derived pine needle biochar) as a biowaste-derived heterogeneous catalyst. The authors applied microwave irradiation (50 W) as a heating source and optimized the reaction conditions through a mixture of the aryl halide 9 (0.5 mmol) and arylboronic acid 30 (1.1 equiv) in the presence of KOPiv (1.2 equiv) as base and Pd/PiNe (0.5 mol%) as catalyst, GVL/H₂O (9:1) as solvent. After 30 min of stirring under MW at 90–120 °C, seventeen bis-aryl products 38 could be obtained in 54–99% yield ([Scheme 17]). Moreover, this new protocol allowed the synthesis of the nonsteroidal anti-inflammatory Fenbufen in nearly quantitative yield, thus promoting a sustainable alternative for accessing this compound. The batch protocol was easily transposed to a continuous flow version using a polytetrafluoroethylene (PTFE) tube filled with the catalyst and irradiated in an MW oven (100–120 °C; 0.1 mL/min). The authors also studied catalyst recovery and reuse, and they related that it is possible to reuse the Pd/PiNe for up to 30 cycles.

Scheme 17 Synthesis of bis-aryl compounds 38 in GVL/H₂O.

In 2021, Wang, Satheeshkumar, and coworkers[40] described a protocol to synthesize thienoquinolines 41, from quinolines 39 (3 mmol) and ethyl mercaptoacetate 40a (1.2 equiv), using GVL as solvent. Fourteen examples were obtained when the reaction was performed in the presence of Et₃N (6 equiv) at 90 °C for 1 h ([Scheme 18]). Thienoquinolines 41 containing electron-withdrawing or electron-donating groups in the phenyl ring could be prepared in moderate to excellent yields (51–92%). The less reactive substrate was the one with the strong electron-withdrawing group CF₃ (R = 7-CF₃), affording 41c in 51% yield. Furthermore, the biological evaluation demonstrated that the synthesized products 41a and 41b presented inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), considered a potential therapy for treating type 2 diabetes and some types of cancer.

Scheme 18 Synthesis of thienoquinolines 41 in GVL.

In the same year, Zhang and Wang[41] developed a rhodium-catalyzed reaction between quinazolinones 42 and vinylene carbonate 43 in GVL to achieve quinazolinone derivatives 44 ([Scheme 19]). Different 2-arylquinazolin-4(3H)-ones 42 (0.2 mmol) reacted with vinylene carbonate 43 (2 equiv) in the presence of AgSbF₆ (10 mol%) and [RhCp*Cl₂]₂ (2.5 mol%) as catalyst in GVL as solvent at 130 °C for 24 h, affording eighteen quinazolinones 44 in moderate to good yields (57–93%). Moreover, a scale-up synthesis of 44a (2 mmol) was performed, furnishing the product in 84% yield. The same strategy, but using mixtures of methanol or ethanol with GVL (1:1), was used to obtain new examples of 6-alcoxy-quinazolinones 44 (R = CH₃ or C₂H₅) in 74–82% yield. However, when n-propanol, isopropanol, or tert-butanol were used, the corresponding products could not be obtained.

Scheme 19 Approaches to prepare quinazolinone derivatives 44 using GVL and GVL/H₂O as solvents.

Still in 2021, Zhang and colleagues[42] developed a new protocol applying rhodium catalysis to synthesize isoquinoline derivatives 47 ([Scheme 20]). The optimal conditions involve the reaction of equimolar amounts (0.2 mmol) of hydroxy-oxime 45 and alkyne 46 in the presence of KOAc (0.2 equiv), AgSbF₆ (8 mol%) and [RhCp*Cl₂]₂ (2 mol%) as catalyst, and GVL as solvent. Seventeen examples of isoquinolines 47 were obtained in 28–88% yield. When 1,4-diacetylenes were used as substrates, alkynyl-functionalized isoquinolines, such as 47c and 47d, were obtained, which could be further submitted to other reactions.

Scheme 20 Synthesis of functionalized isoquinolines 47 in GVL.

In 2024, Chu and coworkers[43] described the synthesis of furfural 49a in 81% yield from the dehydration of xylose 48a. The reaction was catalyzed by a phosphotungstic acid-functionalized biochar catalyst (PTA-BC). After the optimization studies, the best condition was found by stirring a mixture of xylose 48a (0.2 g) and the catalyst PTA-BC (0.1 g) in a mixture of GVL/H₂O (4:1) as solvent at 180 °C for 20 min ([Scheme 21]). The authors performed catalyst reuse tests, but they did not obtain significant results after the third reuse experiment.

Scheme 21 Synthesis of furfural 49a in GVL/H₂O.

In 2024, Malakar and coworkers[44] described the synthesis of indazoles 50, through a multicomponent reaction between bromobenzaldehydes 29, amines 2, and sodium azide ([Scheme 22]). The reaction was carried out using bromobenzaldehyde 29 (1 equiv), amine 2 (1.1 equiv), and sodium azide (1.5 equiv) in the presence of CuI (10 mol%) as catalyst and GVL as solvent, at 100 °C for 10 h. The reaction scope was evaluated employing aniline and mono-, di-, and tri-substituted aromatic amines 2, and the products were obtained in good-to-excellent yields. The scope of the aromatic aldehydes was evaluated, and the corresponding products 50a–e were formed in 75–96% yield. Furthermore, the authors emphasized that GVL has a dual role in this protocol, acting both as a solvent and a ligand in forming a complex with copper salt.

Scheme 22 MCR for the synthesis of indazoles 50 in GVL as solvent.

 

MissingLinkText

2.3

2-Methyl Tetrahydrofuran

Gusevskaya and coworkers[45] published in 2020 a study on the behavior of various eco-friendly solvents for the hydroformylation reaction of the sesquiterpenes caryophyllene oxide 51a and β-caryophyllene 53a. Among the evaluated solvents, 2-MeTHF and p-cymene presented excellent performance. In the case of caryophyllene oxide 51, it was reacted (4 mmol) in the presence of [Rh(cod)(OMe)]₂ (5 μmol) as catalyst, (2,4-di- ^t BuPhO)₃P (10 μmol) as ligand, in 20 mL of 2-MeTHF or p-cymene, under 80 atm of syngas (CO/H₂) at 100 °C for 24 h ([Scheme 23]). The conversion established by gas chromatography-mass spectrometry (GC-MS) analysis was 98% in both solvents. With regard to β-caryophyllene 53a (4 mmol), PPh₃ was used as ligand instead of (2,4-di- ^t BuPhO)₃P at 60 °C. In 2-MeTHF, the substrate 53a was 73% converted into a mixture of mono-hydroformylated 54a and di-hydroformylated 54b (54a:54b ratio = 78:5). When p-cymene was used as solvent, the substrate conversion was 71%, and the 54a:54b ratio = 78:5.

Scheme 23 Hydroformylation of sesquiterpenes using 2-MeTHF as solvent.

In 2020, Cai and coworkers[46] described a multicomponent reaction (MCR) Pd-catalyzed cyclocarbonylation reaction between acyl chlorides 1, iodoanilines 2, and CO. A 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)₂] was used as catalyst, promoting the formation of forty-one 2-substituted 4H-benzo[d][1,3]oxazin-4-ones 55 in 62–97% yield. The best reaction condition was found stirring a mixture of acyl chloride 1 (1 mmol), iodoaniline 2 (1 mmol), under 20 bar of carbon monoxide, N,N-diisopropyl-ethylamine (DiPEA, 3 mmol) as base, and 2N-MCM-41-Pd(OAc)₂ (2 mol%) as catalyst in 2-MeTHF (5 mL) as solvent at 100 °C for 24 h ([Scheme 24]).

Scheme 24 Synthesis of 4H-benzo[d][1,3]oxazin-4-ones 55 in 2-MeTHF

In the same year, Bayer and coworkers[47] published a work on Pd-catalyzed couplings employing renewable bio-based solvents, such as 2-MeTHF, limonene, and α-pinene. This study explored three types of reactions: (a) the carbonylative coupling of boronic acids and aryl bromides; (b) aminocarbonylation; and (c) alkoxycarbonylation reactions. For the carbonylative coupling of boronic acids 30 and aryl bromides 9, the best reaction conditions were found using the catalytic system based on Pd(acac)₂ (5 mol%) and di(1-adamantyl)-n-butylphosphine hydroiodide (CataXCium AHI, 10 mol%) as ligand. Carbon monoxide was generated in situ from 9-methyl-9H-fluorene-9-carbonyl chloride (COgen, 2 equiv), in the presence of 1 M aqueous NaOH to form in situ the respective aryl trihydroxyborates. The best solvent for this reaction was limonene, which represents a good alternative to toluene, which is commonly used in these reactions. Sixteen examples of diaryl ketones 56 were obtained in 40–96% yield, after 18 h at 80 °C ([Scheme 25], Eq. A). In the case of the aminocarbonylation of aryl bromides 9, the study was carried out with differently substituted amines 3, and COgen (2 equiv) in the presence of Et₃N (3 equiv), Pd(OAc)₂ (2 mol%) as catalyst, and 4,5-bis(diphenylphosphino)-9,9-dimethyl−xanthene (XantPhos, 10 mol%) as ligand. Limonene and dimethyl carbonate (DMC) were the best solvents for this reaction, affording 20 aryl amides 3, in 35–99% yield ([Scheme 25], Eq. B). Finally, for the alkoxycarbonylation reaction, aryl bromides 9 were reacted with sodium tert-butoxide in the presence of COgen under similar conditions previously described for the aminocarbonylation of aryl bromides 9. In this case, the palladium species was Pd(dba)₂ (5 mol%) in the presence of 1,1′-bis-(diisopropylphosphino)ferrocene (dippf, 5 mol%) as the ligand. Among the evaluated bio-based solvents, α-pinene and 2-MeTHF proved to be the most suitable for the reaction, providing the respective tert-butyl aryl esters 25 in 45–98% yield ([Scheme 25], Eq. C).

Scheme 25 Synthesis of diaryl ketones 56 (Eq. A), aryl amides 3 (Eq. B), and aryl esters 25 (Eq. C).

In 2021, Meninno, Lattanzi, and coworkers[48] described a telescoping synthesis of cyclic amidines 58 with three stereogenic centers in good-to-excellent yields and high diastereoselectivity. In this metal-free one-pot process, 2-MeTHF and diethyl carbonate (DEC) were employed through a three-step reaction ([Scheme 26]). Firstly, a Knoevenagel condensation occurs between 2-(phenylsulfonyl)acetonitrile 5a and aldehydes 29, in the presence of N,N-disopropyl ethylamine (DIPEA) as base and diethyl carbonate (DEC) as solvent at 50 °C for 4–10 h, affording the alkyne intermediate species. After the disappearance of the starting materials, the tert-butyl ester glycinate benzophenone Schiff base 57 is added, thus reacting with the previously formed alkyne through a Michael addition at 50 °C for 24–48 h. Once the reaction was completed, the solvent was removed, and 2-MeTHF and HCl 2N were added to the last step of hydrolysis and cyclization. Nineteen amidines 58, bearing electron-withdrawing and -donating groups, cyclic and heterocyclic substituted, with the majority of trans–trans diastereoisomer conformation, were obtained in 44–89% yield. Additionally, a gram-scale reaction was conducted, using 1 g of phenyl sulfonylacetonitrile, affording 58a in 60% yield, only trans–trans conformation. Moreover, some products (58a–c) were submitted to the acetylation reaction, furnishing the corresponding acylated products 59a–c in good yields. Finally, the compound 58a reacted with methyl acrylate 10a, forming the species 60a in 69% yield.

Scheme 26 Synthesis and chemical reactivity of cyclic amidines 58.

In 2024, Takács and coworkers[49] described a study of the Pd-catalyzed aminocarbonylation reaction using three different bio-based solvents: 2-MeTHF, ethyl levulinate (EtLev), and methyl levulinate (MeLev). The reaction was carried out using a variety of substituted aryl iodides 9 (0.5 mmol) and amines 2 (1.5 equiv) in the presence of Pd(OAc)₂ (2.5 mol%), XantPhos (2.5 mol%), triethylamine (0.25 mL), and 5 mL of solvent under a CO atmosphere (1 bar), at 50 °C for 6 h ([Scheme 27]). Substrate conversions were determined by GC, and a range of 3% to 100% yield of aryl amide 61 was observed. For the examples in which the substrate conversion did not reach 100%, it was found that levuninates performed better than 2-MeTHF as a solvent.

Scheme 27 MCR for the synthesis of aryl amides 61.

 

MissingLinkText

2.4

Dimethyl Isosorbide

Lei, Jin, and coworkers[50] developed in 2022 a nickel-catalyzed reductive cross-coupling of substituted aryl 9 or heteroaryl bromides 62 with vinyl acetate 10b, affording a wide range of vinyl arenes 11 and heterovinyl arenes 63. After optimization studies, the best reaction condition was encountered using aryl bromide 9, an excess of vinyl acetate 10b (2 equiv), NiCl₂(dppp) (0.1 equiv), Zn (2 equiv), and lithium iodide (3.5 equiv) in dimethyl isosorbide (DMI) as solvent. The reaction mixture was stirred at 65 °C for 8 h, affording fifty-four vinyl arenes and heteroarenes examples, with yields ranging from 52% to 99% ([Scheme 28]). Aryl bromides 9 and heteroaryl bromides 62 containing electron-donating or electron-withdrawing substituents on the phenyl ring, were suitable substrates for the reaction. Moreover, the authors explored the synthesis of different di- and tri-vinyl arenes 64 by using an excess of vinyl acetate, obtaining the expected products in good yields.

Scheme 28 Synthesis of vinyl arenes 11 and heterovinyl arenes 63 using DMI as solvent.

 

MissingLinkText

 

MissingLinkText

3

Terpene- and Lignan-Based Solvents

Terpenes are naturally occurring compounds built from isoprene units, primarily derived from higher plants. This diverse class encompasses over 55,000 distinct structures. These structures play a significant role in organic chemistry, biochemistry, and medicine.[51] They are classified according to the number of isoprene units in their structure, and these are hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), tetraterpenes (C40), and polyterpenes (C5) _n with n > 8. They can be acyclic or cyclic, being mono-, bi-, tri-, tetra-, and penta-cyclic with rings of 3–14 members. Mono- and sesquiterpenes can be found, predominantly, in plant raw materials, such as essential oils; sesqui-, di-, and triterpenes in balsams and resins; tetraterpenes in carotenoids; and polyterpenes in latex.[52] [53] Terpene biosynthesis occurs in different cellular parts of the plant, such as plastids, mitochondria, and cytosol, where a group of enzymes catalyzes the conversion of hydrocarbon diphosphates into their skeletons. Subsequently, they may suffer additional rearrangements and oxidations to transform them into alcohols, glycosides, ethers, esters, aldehydes, ketones, and carboxylic acids.[53] This section is dedicated to the use of terpenes as solvents in organic synthesis, and the terpenes that have been described herein are eucalyptol, limonene, p-cymene, and sabinene ([Fig. 2]).

Fig. 2 Terpene-based solvents.

3.1

Eucalyptol

Eucalyptol, or 1,8-cineole, a bio-based monoterpene, had been explored as a novel solvent for organic transformations, specifically in Migita–Kosugi–Stille palladium-catalyzed cross-coupling reactions in the synthesis of several heterocyclic systems. This solvent has proven to be a viable alternative to conventional options commonly employed in these reactions.

In 2019, Berteina-Raboin, Scherrmann, and Campos[54] proposed for the first time the use of eucalyptol as a bio-based solvent to form heterocycles containing oxygen, sulfur, and nitrogen in the Suzuki–Miyaura and Sonogashira–Hagihara reactions ([Scheme 29]). The authors studied the condensation reaction between 2-aminopyridine 65a and different 2-bromoacetophenones 66 at 105 °C for 22 h, affording five differently substituted products 67 in 63–91% yield ([Scheme 29], Eq. A). Moreover, a one-pot protocol was developed to prepare 2-(4-fluorophenyl)-3-arylimidazo[1,2-a]pyridines starting from 65a and 1-(4-fluorophenyl)ethan-1-one 66a, followed by the addition of aryl bromides 9. Six examples of 2-(4-fluorophenyl)-3-arylimidazo[1,2-a]pyridines 67 were obtained in 58–99% yield after stirring at 150 °C for 24 h (Eq. B, [Scheme 29]). The Suzuki–Miyaura reaction was performed using various substrates, such as 4-chlorothieno[3,2-d]pyrimidine 68a, 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine 70a, 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine 72a, 6-chloro-[1,2,4]triazolo[4,3-a]pyrazine 73a and 4-chlorofuro[3,2-c]pyridine 76a, and different boronic acids 30, reaching the products 69, 71, 74a, 75a, and 77 in good-to-excellent yields ([Scheme 29], Eqs. C–F). Finally, the Sonogashira–Hagihara reaction was accomplished with 4-chlorothieno[3,2-d]pyrimidine 68a or 4-chlorofuro[3,2-c]pyridine 76a with different alkynes 46, giving the corresponding products 78 and 79 in good yields ([Scheme 29], Eqs. G and H). No reaction was observed when 7-chloro-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine were used as starting materials.

Scheme 29 Eucalyptol as a solvent in the synthesis of functionalized heterocyclic compounds.

Still in 2019, the same group[55] published another work on the use of eucalyptol as solvent to prepare oxygen-, sulfur-, and nitrogen-containing heterocycles 81, 83, 85, 88, and 89 through the Buchwald–Hartwig coupling reaction. The alternative solvent was found to be a suitable substitute for the common solvents, such as toluene, xylene, THF, and DMF. Secondary amines 2 were reacted with different aryl and heteroaryl substrates, like 2-bromoflurene 80a ([Scheme 30], Eq. A), 4-bromo-1,2-methylenedioxybenzene 82a ([Scheme 30], Eq. B), 6-bromo-2methylquinoline 84a ([Scheme 30], Eq. C), 7-bromo-6-phenylthienol[2,3-bb]pyrazine 86a ([Scheme 30], Eq. D), and 3-bromo-2-phenylthienol[3,2-b]pyridine 87a ([Scheme 30], Eq. D). The reactions were carried out in the presence of Pd(OAc)₂ (5 mol%), BINAP (10 mol%) as ligand, and Cs₂CO₃ (2 equiv) as base, at 110 °C, for 17–30 h. A total of twenty-three compounds were obtained in 43–99% yield.

Scheme 30 Synthesis of fused ring systems using eucalyptol as solvent.

In 2020, Campos and Berteina-Raboin[56] described the reaction of hetero-tributylstannyl derivatives 90 with several N-heterocycles, like 4-chlorothieno[3,2-d]pyrimidine 68a, 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine 72a, 6-chloro-[1,2,4]triazolo[4,3-a]pyrazine 73a, and 4-chlorofuro[3,2-c]pyridine 76a, resulting in the corresponding products 69, 74, 75, and 77 in moderate-to-good yields ([Scheme 31]). A limiting factor of the reaction was noted when 7-chloro-5-methyl [1,2,4]triazolo[1,5-a]pyrimidine 91a was used, which was not able to afford the expected coupling product. Furthermore, the authors highlighted that eucalyptol could be efficiently recovered via distillation under reduced pressure and reused in new reactions, positioning it as an attractive and sustainable alternative to traditional solvents.

Scheme 31 Synthesis of nitrogen-containing heterocycles using eucalyptol as solvent.

In the same year, Berteina-Raboin and coworkers[57] described the sequential Buchwald–Hartwig coupling/pyridine dearomatization reaction to synthesize benzo-fused 11H-pyrido[2,1-b]quinazolin-11-ones 93, using eucalyptol instead of traditional oil-based solvents. The authors highlighted the importance of replacing standard solvents with safer alternatives and good ecological impact. In a typical procedure, a mixture of methyl anthranilate 92 and 2-bromo-pyridine 7 (2 equiv) in the presence of Pd(OAc)₂ (3 mol%), Xantphos (4 mol%), and Cs₂CO₃ (2.5 equiv) in eucalyptol as solvent, was stirred at 120 °C for 18–24 h ([Scheme 32]). A total of fourteen compounds were prepared in 39–96% yield. No reaction occurred when 2-bromo-5-chloropyridine and 2-bromo-5-methoxypyridine were employed as substrates in the reaction with methyl 6-amino-1H-indazole-7-carboxylate, and products 93d and 93e were not formed.

Scheme 32 Synthesis of benzo-fused 11H-pyrido[2,1-b]quinazolin-11-ones 93 in eucalyptol.

In 2021, the same group[58] reported three different applications of eucalyptol as solvent: in a MCR, in Hiyama coupling, and in the cyanation of heterocycles, to furnish oxygen-, sulfur-, and nitrogen-containing heterocycles. Firstly, from the reaction of aldehydes 29 with pyrrolidine 2a (2 equiv) and malononitrile 5b (2 equiv) for 24 h at 100 °C, were prepared six different 2,4-dicyano anilines 94a–f in 45–68% yield ([Scheme 33], Eq. A). Moreover, five different amines 3 reacted with para-tolualdehyde 29b to form products 94g–j in 57–75% yield ([Scheme 33], Eq. B). Through the Hiyama-coupling of 7-chlorothieno[3,2-b]pyridine 68a and 4-chlorofuro[3,2-c]pyridine 76a with different trimethylsilyl derivatives 95, the authors obtained eight coupling products in 30–81% yield (six thienyl-derivatives 78 and two furyl ones 79), after stirring for 30–48 h at 100 °C ([Scheme 33], Eqs. C and D). Finally, 7-bromo-6-phenylthieno[2,3-b]pyrazine 87a was submitted to the Pd-catalyzed cyanation reaction with Zn(CN)₂ (0.6 equiv) at 140 °C after 27 h to produce 6-phenylthieno[2,3-b]pyrazine-7-carbonitrile 89d in 72% yield ([Scheme 33], Eq. E). In this work and in the previous ones, the authors commented that it was possible to recover 70% of the solvent.

Scheme 33 Eucalyptol as solvent in MCR (Eqs. A and B), Hiyama-coupling (Eqs. C and D), and in Pd-catalyzed cyanation (Eq. E).

In 2024, Raboin-Berteina and coworkers[59] described the synthesis of quinazolines 98 using green solvents such as eucalyptol and sabinene. Their studies revealed that the optimal reaction conditions involved stirring a mixture of equimolar amounts of 96 and 97 in the appropriate solvent at 130 °C under conventional heating (oil bath) for 96 h. Although microwave irradiation was evaluated, it did not yield satisfactory results. Under the optimal conditions, sixteen examples of quinazolines 98 could be obtained, with yields ranging from 23% to 94% ([Scheme 34]). It is important to emphasize that, according to the authors, the products 98 were obtained through simple filtration—a process that was significantly easier when eucalyptol was used as the solvent compared to sabinene.

Scheme 34 Synthesis of quinazolines 98 using eucalyptol or sabinene as solvent.

In 2022, Dave et al.[60] described the Michael addition reaction of indoles 31 to α,β-unsaturated ketones 27 and nitrostyrene 11g using eucalyptol as solvent and Fe(OTs)₃·6H₂O (15 mol%) as a green catalyst. After stirring the mixture at 100 °C for 26–60 min, a total of twenty-three adducts 99 could be obtained in 65–89% ([Scheme 35]). Eucalyptol was reused for up to four reactions without a substantial decrease in yields.

Scheme 35 Michael-addition of indoles to electron-deficient alkenes using eucalyptol as solvent.

In 2023, Ghosh and coworkers[61] described the synthesis of 2,3-dihydroquinazolin-4(1H)-ones 44 and isoxazolone derivatives 102 from several aldehydes 29 by using eucalyptol as solvent. The optimal reaction condition to prepare 2,3-dihydroquinazolin-4(1H)-one 44 was encountered using equimolar amounts of benzaldehyde 29, isatoic anhydride 100a, and ammonium acetate in eucalyptol at 50 °C for 30 min ([Scheme 36]). Through this reaction, using different aliphatic, aromatic, and heterocyclic-substituted benzaldehydes 29, it was possible to prepare twelve products 44 in 78–86% yield. Moreover, eucalyptol proved to be a suitable solvent in the reaction between aromatic aldehydes 29, ethyl acetoacetate 101a, and hydroxylamine, leading to nine isoxazolone derivatives 102 in 78–90% yield after 3 h of reaction at room temperature ([Scheme 36]).

Scheme 36 Synthesis of dihydroquinazolinones 44 and isoxazolones 102 in eucalyptol.

 

MissingLinkText

3.2

Limonene

In 2019, Suginome and coworkers[62] reported the use of limonene as a bio-based solvent due to its chirality, which gave the configuration imbalance to the catalyst, allowing the reactions to occur. The catalyst employed was poly(quinoxaline-2,3-diyl)s bearing 2-(diphenylphosphino)phenyl moieties and it was applied in the asymmetric collaborative C−C bond cleavage of (1R,6S)-7-methylenebicyclo[4.1.0]heptane 103a in (S)-limonene, which allowed a yield of 47% and an enantiomeric excess (ee) of 89% of the corresponding product 104a ([Scheme 37]). In the same work, the authors also used a mixture of (R)-limonene and THF in the hydrosilylation of styrene 11a and, after 24 h at room temperature, trichloro(1-phenylethyl)silane 105a was achieved in 89% yield with 95% of ee. Moreover, they investigated the reaction between dimethyl (1-bromonaphthalen-2-yl)phosphonate 106a and (4-methylnaphthalen-1-yl)boronic acid 30c to form dimethyl (4′-methyl-[1,1′-binaphthalen]-2-yl)phosphonate 107a, evaluating different ligands and various mixtures of limonene, both R and S, with THF. After 24 h of reaction at room temperature, yields of 55% to 69% and ee of 70–98% could be obtained.

Scheme 37 (S)- and (R)-Limonene in Pd-catalyzed coupling reactions.

In 2023, Liu et al.[63] used molecular theoretical calculations to determine the dipole moment of conventional solvents used in the condensation of carboxylic acids with amines to prepare amides and observed that this property has little effect on the condensation yield. In this theoretical study, the authors observed that the polarity of limonene could solubilize the reagents in the model reaction to prepare N-phenylbenzamide 3n from benzoic acid 20a and aniline 2b, while the product precipitates in the reaction medium. This hypothesis was tested in the reaction between equimolar amounts of different carboxylic acids 20 and amines 2, in the presence of 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.2 mmol) and N-diisopropylethylamine (DIPEA, 2 mmol) as coupling reagent ([Scheme 37]). It was possible to access thirty-two products in 40–97% yield after 2 h of reaction at 60 °C. The reaction worked well with a wide range of substrates, including aromatic and aliphatic carboxylic acids and aromatic and aliphatic amines. Through this strategy, compounds 3o and 3p, which are activators of tyrosine phosphatase (SHP1), a key regulator of immune cell function, were prepared in 60% and 40% yield, respectively. This result substantially improves the synthesis of 3o and 3p, obtained previously in 36% (55% in gram-scale) and 26%, respectively.[64] Noteworthy, all the prepared compounds were purified by simple filtration without any other process. Moreover, the solvent could be recovered and reused up to six times without efficiency loss.

Scheme 38 Limonene as a solvent in the synthesis of amides 3.

 

MissingLinkText

3.3

p-Cymene

Thompson and Ye[65] reported the use of bio-based p-cymene in the direct arylation-polymerization of 108a with 109, and 108b with 111a to synthesize the polymers 110 (3 examples, 72.6–96.2% yield) and 111b (55.8% yield). The reaction was carried out using Pd(OAc)₂ (4 mol%) as catalyst, P(o-anisyl)₃ (16 mol%) as ligand, Cs₂CO₃ (3.2 equiv) as base, and neodecanoic acid (NDA, 1.0 equiv) as an additive. The desired polymers were obtained after stirring the reaction mixture for 24 h at 110 °C, avoiding highly toxic organotin by-products and the use of oil-based, commonly used solvents THF, toluene, or dimethylacetamide ([Scheme 39]).

Scheme 39 Arylation-polymerization reactions using p-cymene as solvent.

In 2021, Lei, Szostak, and coworkers[66] developed a study on the behavior of the Suzuki–Miyaura cross-coupling reaction of N-Boc-amides 3 with boronic acids 30 in several green solvents. Among the evaluated solvents were methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), diethyl carbonate (DEC), p-cymene, dimethylcarbonate (DMC), i-PrOAc, and anisole. The best in class was i-PrOAc, with p-cymene presenting good performance in two of the ten tested reactions. The reaction was conducted by stirring a mixture of amide 3, aryl boronic acid 30 (2 equiv) in the presence of [Pd(IPr)(cin)]Cl (3 mol%), K₂CO₃ (3 equiv), and H₂O (5 equiv) in p-cymene at 23 °C for 15 h, to afford the ketones 56 ([Scheme 40]).

Scheme 40 Synthesis of diaryl ketones 56 in p-cymene.

 

MissingLinkText

3.4

Sabinene

In 2023, Bereina-Raboin and coworkers,[67] after studying in depth the use of eucalyptol as a bio-based solvent (see Section 3.1), described the use of sabinene in the synthesis of thiazolo[5,4-b]pyridines 112 under both thermal heating (oil bath) and microwave irradiation ([Scheme 41]). Different isothiocyanates 97 reacted with 3-amino-2-chloropyridine 65b at 100 °C for 16 h under conventional heating or at 130 °C for 2 h under MW ([Scheme 41]). Good results were obtained in both methodologies, except in the case of product 112a, which was formed in 50% under conventional heating, but under MW irradiation, the pyrolysis of the reagents was observed. The best result using conventional heating was obtained in the synthesis of 112g (67% yield), while 2-chloro-5-methylpyridin-3-amine 112b was obtained in 66% yield under MW irradiation.

Scheme 41 Synthesis of thiazolo[5,4-b]pyridines 112 using sabinene as solvent.

 

MissingLinkText

3.5

Mesesamol

A new promising lignan-related bio-based solvent is worth mentioning in this review: mesesamol. In 2023, Kupai and coworkers[68] reported its synthesis, its use as a green solvent in different organic reactions, and a study on its properties and characteristics. Mesesamol was obtained in 90% yield from sesamol, through a green methylation reaction with DMC, in the presence of DBU (1.5 equiv), after 3 h of reaction at 90 °C (Eq. A, [Scheme 42]). Then, it was studied in the Suzuki–Miyaura reaction between different aromatic halides 9 with phenylboronic acids 30 in the presence of Pd(dppf)Cl₂ as catalyst. The corresponding coupled products 38 were reached in 48–87% yield (calculated by NMR analysis) after 5 h at 80 °C (Eq. B, [Scheme 42]). Moreover, mesesamol was employed as a solvent in the Sonogashira reaction of iodobenzene 9a and phenylacetylene 46a to form the product 46b in 82% yield, after 1 h at room temperature, under a nitrogen atmosphere (Eq. C, [Scheme 42]). Additionally, two cinchona alkaloid-derived thiourea organocatalysts were prepared in quantitative yield from isothiocyanate 97 and cinchona amin (Eq. D, [Scheme 42]). Finally, these organocatalysts were used in the asymmetric Michael addition of acetylacetone 101b to trans-β-nitrostyrene 11g (Eq. E, [Scheme 42]), affording the corresponding adduct in high yield and ee. The authors highlighted that mesesamol is a valid alternative to the conventional solvent dichloromethane.

Scheme 42 Synthesis of mesesamol (Eq. A) and its application in several chemical transformations.

 

MissingLinkText

 

MissingLinkText

4

NaDES Bio-based Solvents

Deep eutectic solvents (DESs) are formed by mixing a hydrogen bond donor and a hydrogen bond receptor in different proportions.[69] The resulting mixture has an extremely low melting point compared to the original substances. Typical H-bond donors are organic acids, sugars, alcohols, and terpenoids, while choline chloride (ChCl), amino acids, and ammonium salts are suitable H-bond acceptors.[70] Also known as third-generation ionic liquids, DESs are less toxic and cheaper and are considered a greener alternative to ionic liquids of the first and second generations.[71] First described by Verpoorte and coworkers in 2011,[72] natural deep eutectic solvents (NaDESs) are a special class of DESs, composed of blends of primary metabolites in specific proportions. Their supramolecular structure arises primarily from hydrogen bonds between the constituent molecules.[73] The nontoxic and eco-friendly nature of NaDESs make them suitable for applications in food, cosmetic, agrochemical, and pharmaceutical industries. The usefulness of NaDESs is based on their wide range of polarities, from being more polar than water to equivalent to methanol. Therefore, it can solubilize a variety of low- to medium-polarity compounds that are insoluble or poorly soluble in water. Additionally, this year, Chapeland-Leclerc, Chevé-Kools, and coworkers[74] published a deep and detailed work on the use of NaDESs as green solvents in the pharmaceutical industry.

This section is dedicated to the use of NaDESs as solvents in organic synthesis. Works where at least one of the components of the deep eutectic used is not natural will not be covered here, i.e., the term NaDESs is used in a different way to the one defined above.

In 2022, Detsi and coworkers[75] described the synthesis of several aurone (2-benzylidenebenzofuran-3(2H)-one) derivatives 114 through the Knoevenagel condensation of benzofuranone 113a and benzaldehydes 29 under sonication. Four different NaDESs were prepared and tested in a model reaction using vanillin 29c as the aldehyde counterpart: l-proline/glycerol 1:2, l-proline/oxalic acid 1:1, l-proline/d, l-lactic acid/water 1:2:2.5, and ChCl/glycerol 1:2 (known as glyceline). The best results were obtained using l-proline/glycerol 1:2 (Pro/Gly, 2.0 g/mmol), which works both as a solvent and a catalyst in the Knoevenagel reaction. In the optimal reaction conditions, an equimolar mixture of the reagents 113a and 29 in the NaDES was sonicated for 8–18 min using a US probe (30% of amplitude, 120 W). By this procedure, a total of nine aurone derivatives 114 were obtained in 62–89% yield, with most of the compounds being purified by simple filtration after addition of water to the reaction crude ([Scheme 43]). The best result was obtained using vanillin as starting aldehyde, affording the derivative 114a in 89% yield after 12 min. Good results were also obtained using heteroaromatic aldehydes, like 2-thyenyl, which gave 114b in 59% yield. The less reactive benzaldehyde was ortho-anisaldehyde, which reacted with benzofuranone 113a to form aurone 114c in 56% yield after 18 min of sonication. The recyclability of the NaDESs was examined in the synthesis of 114a, revealing that Pro/Gly could be used up to seven times without a substantial decrease in the reaction yield.

Scheme 43 Use of Pro/Gly as solvent to prepare aurone derivatives 114.

Still in 2022, Perrone and coworkers[76] described the Pd-catalyzed homocoupling reaction of aryl and heteroaryl chlorides using glyceline as the solvent (1.0 g/mmol). The optimal condition involves stirring a mixture of the aryl/heteroaryl chloride 9, Pd/C (10 mol%), and Ca(OH)₂ (10 equiv) in glyceline at 80 °C for 12 h. A total of twenty (hetero)biaryls 8 were obtained in moderate-to-excellent yields, including the marketed drug Abametapir, which was prepared in 74% yield. According to the authors, glycerol present in the NaDESs can act as a green organic reductant, thus avoiding the use of external reducing agents, like metals. The recyclability of the catalyst/NaDES system was evaluated in the homocoupling of 2-chloro-5-(trifluoromethyl)pyridine 9b. After the first reaction, bipyridine 8f was extracted with cyclopentyl methyl ether and more reagent 9b was added to the remaining reaction medium. This protocol was successively repeated for up to four reactions, giving 8f in 87%, 83%, 70%, and 63% yields. In the fifth reuse, the yield drastically dropped to 35% ([Scheme 44]).

Scheme 44 Glyceline as solvent in the Pd-catalyzed homocoupling of aryl and heteroaryl chlorides.

Thiery, Delaye, and coworkers[77] described, in 2023, the combination of mechanochemical with glyceline in the liquid-assisted grinding (LAG) Suzuki–Miyaura cross-coupling reaction between bromoarenes 9 and boronic acids 30. In this study, several solvents were tested, including other DES, like ChCl/ethylene glycol, ChCl/urea, and glycerol/urea, and the best in class was glyceline. The optimal reaction conditions involve milling (milling balls of ZrO₂, ∅ 5mm, 10 g) a mixture of equimolar amounts of the aryl bromide 9 and the boronic acid 30, Pd(OAc)₂ (1 mol%) and Na₂CO₃ (1.25 equiv), in the presence of glyceline (0.5 g/mmol) at 2000 rpm for 10 min. By this procedure, nineteen diaryl derivatives 38 were prepared in 31–82% yield after 10–20 min of reaction. The best yield was obtained using 2-bromonaphthalene and p-methoxyphenylboronic acid, affording 2-(4-methoxyphenyl)naphthalene 38f in 82% yield. A moderate yield (65%) was obtained for 38g, derived from p-fluorophenylboronic acid, while no reaction occurred starting from mesityl, benzyl, or n-hexylboronic acid ([Scheme 45]). A very good performance was observed when the protocol was applied to the gram scale, with product 38h being obtained in 90% (2.05 g) yield after 20 min, an expressive improvement to the so far available methods.

Scheme 45 Suzuki–Miyaura cross-coupling in glyceline.

In 2024, Tabasso and coworkers[78] described an eco-friendly microwave-assisted route to access N-substituted 5-methyl-2-pyrrolidones through the reductive amination of levulinic acid. Authors have prepared two NaDESs: ChCl/lactic acid 1:1 (ChLA) and ChCl/malic acid 1:1 (ChMA), which were tested in the reaction using different H-donor agents: HCO₂H, NH₄HCO₂, and (EtO)₃SiH. To determine the best reaction conditions, the reaction between equimolar amounts of levulinic acid 115a and p-anisidine 2c was used, aiming to prepare 1-(4-methoxyphenyl)-5-methylpyrrolidin-2-one 116a. In all the tested reducing systems, ChLA presented the best performance, using a 115a/2c/H-donor ratio of 2:4:4 and 20 mol% of ChLA under MW irradiation. Quantitative yields of 116a were obtained after 1 h of irradiation using formic acid (180 °C) and 10 min using (EtO)₃SiH (80 °C). The best condition using (EtO)₃SiH was extended to other aromatic and aliphatic amines, affording a total of nine N-substituted 5-methyl-2-pyrrolidones 116 in good-to-excellent yields ([Scheme 46]). The method was successfully applied to both aromatic and aliphatic anilines, with quantitative yields being obtained in some cases (p-anisidine and pyrrolidine), with the lower yield being observed when p-nitroaniline was used (116b, 55%). The authors used a synergic effect of MW and ChLA to justify the excellent performance of NaDESs in the reaction.

Scheme 46 Synthesis of N-substituted 5-methyl-2-pyrrolidones 116 in ChLA.

Despite the focus of this review being the use of alternative, bio-based substances as solvents in organic synthesis, there are several papers where NaDESs can act both as solvents and catalysts/promoters of the reaction. The next two papers are about the use of NaDESs as catalysts in solvent-free reactions or under solvent-minimized synthesis. These are interesting examples of the versatility of NaDESs in organic synthesis.

In 2024, Shirini and colleagues[79] described the use of an equimolar mixture of ChCl and glutamic acid (ChCl:Glu 1:1) as a catalyst (10 mol%) in MCRs to prepare isoxazol-5(4H)-one 102 and 1,2,4-triazoloquinazolinone derivatives 119. The reactions were performed both under solvent-free conditions and in the presence of a few drops of water. To prepare isoxazol-5(4H)-one derivatives 99, a mixture of aryl aldehydes 29, ethyl acetoacetate 101a, and hydroxylamine hydrochloride (1.2 equiv) was stirred at 70 °C for 16–40 min in the presence of ChCl:Glu 1:1 (10 mol%) and a few drops of water. A total of twelve differently substituted isoxazol-5(4H)-ones 102 were obtained in 84–94% yield, starting from aromatic and heteroaromatic aldehydes (Eq. A, [Scheme 46]). The authors did not observe a clear influence of electronic effect in the benzaldehyde derivatives, with very good yields being obtained for both electron-rich and electron-poor aldehydes. Excellent yields were also obtained when heteroaromatic aldehydes (furyl and pyrrolyl) were used (Eq. A, [Scheme 47]). The 1,2,4-triazoloquinazolinones 119 were obtained after stirring equimolar amounts of aldehyde 29, 3-amino-1,2,4-triazole 117a, dimedone 118a, or 1,3-cyclohexanedione 118a′ in the presence of ChCl:Glu 1:1 (10 mol%) at 100 °C for 10–15 min. This protocol was used to prepare eighteen 1,2,4-triazoloquinazolinones in 85–93% yield, starting from different aromatic aldehydes, including nicotinaldehyde, which afforded 119a in 85% yield after 17 min of reaction. Similar to the observed for the isoxazol-5(4H)-ones, the reaction was suitable for differently substituted benzaldehyde derivatives regardless of the substitution pattern (Eq. B, [Scheme 47]).

Scheme 47 Synthesis of isoxazol-5(4H)-ones 102 and triazoloquinazolinones 119 in ChCl/Glu.

Still in 2024, Cheraiet and coworkers[80] described a close-related work to prepare isoxazol-5(4H)-one derivatives 102, through the MCR mediated by NaDESs betaine/citric acid/water 1:1.5:1, Bet/CA. The reactions were performed as described in Eq. A, [Scheme 46], using 0.5 mL/mmol of water as solvent in the presence of 2 mol% of the betaine-based NaDESs. The authors tested three different reaction conditions: heating at 40 °C (oil bath), irradiation with microwave (MW), and sonication (US). A drastic reduction in the reaction time was observed when the reaction was conducted under MW compared to thermal heating and US, from 5–15 min to 3–40 s. This reduction in time did not result in reduced yields of product 102. For instance, 102d, derived from unsubstituted benzaldehyde 29d, was obtained in 97% yield in 5 min under thermal heating and 10 min under US, while under MW irradiation, only 3 s were necessary. Compared to the method developed almost simultaneously by Shirini and colleagues,[79] this procedure was more general, being successfully used to prepare 4-((1H-indol-3-yl)methylene)-3-methylisoxazol-5(4H)-one (102i, 95% yield) and 3-methyl-4-((4-oxo-4H-chromen-3-yl)methylene)isoxazol-5(4H)-one (102j, 90% yield), derived from indole and 4H-chromen-4-one, respectively (Eq. A, [Scheme 47]).

In 2021, Giofrè, Tiecco, and coworkers[81] published the use of NaDESs to access 1,2,3-triazoles 121 from azides 120 and alkynes 46 through a copper-catalyzed click cycloaddition. Different NaDESs were investigated, such as choline chloride/urea (ChCl/urea 1:2, m.p. = 12 °C), choline chloride/L-ascorbic acid (ChCl/Asc 2:1, m.p. = 20 °C), choline chloride/oxalic acid (ChCl/Ox 2:1, m.p. = 30 °C), trimethylglycine/oxalic acid (TMG/Ox 1:2, m.p. = 33 °C), and trimethylglycine/glycolic acid (TMG/GA 1:2, m.p. = −36 °C). The best results were obtained using ChCl/Asc and TMG/GA, being possible to achieve eighteen examples of triazoles 121 in 48–96% yield after 24 h of reaction. With both NaDESs, the use of base was unnecessary; however, when TMG/GA was employed as solvent, sodium ascorbate (30 mol%) was used as reducing agent. The reactions using TMG/GA were conducted at 50 °C, while with ChCl/Asc, they could be performed at room temperature ([Scheme 48]). Various substrates 120 and 46 were employed, bearing disparate functional groups, and all of them reacted smoothly. The authors commented that there was a limitation of the reaction: substrates like but-3-yn-1-ol, 1-pentyne, cyclopropyl acetylene, cyclohexenyl acetylene, and 3,3-dimethyl-1-butyne were not soluble in ChCl/Asc and did not react under the reaction conditions.

Scheme 48 Synthesis of 1,2,3-triazoles 121 in TMG/GA or ChCl/Asc as solvent.

In 2022, Petrini, Palmieri, and Lupidi[82] developed a methodology to prepare functionalized quinoxalines 124 using NaDES ChCl/H₂O (1:3.3) as solvent, at room temperature, in only 5 min ([Scheme 49], Eq. A). Additionally, the solvent was recovered and reused six times without loss of efficiency. Various substrates, 1,2-dicarbonyl 122 and 1,2-diamino 123 compounds, were tested and were well tolerated, producing the products 124, including species with acid-sensitive groups or related to them, in 46–96% yield. With unsymmetrical reagent was reached a mixture of products 124a,a′ in 46% overall yield. The authors highlighted that the products were purified by only the extraction step, without needing any further purification process. Furthermore, they calculated green metrics such as process mass intensity (PMI) and environmental factor (E-factor), demonstrating the green aspects of their methodology. Finally, gram-scale reactions were carried out, and the products 124b,c were formed in 97% and 95% yield, respectively.

Scheme 49 Synthesis of functionalized quinoxalines 124 and coumarin-derivatives 126 using NaDESs as solvent.

Another protocol to access quinazoline derivatives 124 was published in 2023 by Hossain’s group using glyceline as solvent.[83] Through a one-pot reaction between 2-bromoacetophenone 66 and 1,2-diaminobenzene 123 (1.2 equiv) for 2 h at 120 °C, it was possible to prepare twenty-two products 124 in 86–96% yield ([Scheme 49], Eq. B). The authors underlined that when a mixture of regioisomers was possible, the 7,2-disubstituted was the major one (60:40). 1,2-Diaminobenzene 123 was also reacted with 3-(bromoacetyl)coumarin 125a, and in this way was possible to achieve coumarin-derivatives 126 in 86–92% yield ([Scheme 49], Eq. C). Moreover, a gram-scale reaction (10 mmol) was carried out, and the product 126a was produced in 78% yield. Noteworthy, the NaDESs can be recovered and reused five times without losing efficiency.

In 2024, Molnar and coworkers[84] reported the microwave-, ultrasound-, and mechanochemical-assisted synthesis of quinazolin-4(3H)-one derivatives 44 and 128, starting from 2-methylbenzoxazin-4-ones 55 and aromatic amines 2 or hydrazides 127. The authors tested 20 different choline chloride-based NaDESs, and glyceline was the best in class, acting both as solvent and catalyst in the reaction ([Scheme 50]). Regarding the energy source, the best results were obtained using a mechanochemistry (ball milling) approach, affording products 44 in a range of 45–87% yield. Under conventional heating, products were obtained in 17–68%, under MW irradiation in 10–41%, and under ultrasound, in 15–56% yield. The amount of used NaDESs was 10 mL/mmol in the conventional, US, and MW procedures and 1 mL in the mechanochemical one, which afforded the higher yields of the desired products. In all cases, a small excess (20%) of aniline 3 or hydrazide 127 was used. The reaction times were 4 h (80 °C, oil bath), 1 h (80 °C, MW or US), and 20 min (ball milling), affording a total of twenty-nine examples. After the reaction was finished, water was added, and the product 44 was purified by recrystallization from ethanol or methanol. Furthermore, the authors conducted a study on the predicted activity through the calculated ADME properties, showing that the prepared compounds are potential anticonvulsants, skeletal muscle relaxants, and antifungal drugs.

Scheme 50 Mechanochemical-assisted synthesis of quinazolin-4(3H)-ones 44 and 128 in glyceline and a plausible mechanism.

In the same year, Hosseinzadeh and colleagues[85] proposed two methods to prepare 2,3-dihydroquinazolin-4(1H)-one derivatives 44, both using ChCl/Asc 1:2 as catalyst (110 mg, 70 mol%). One of the strategies involves reacting equimolar amounts of aldehyde 29 and 2-aminobenzamide 3y for 10–40 min at 60 °C, affording eighteen compounds in 76–97% yield ([Scheme 51], Eq. A). The other approach started from aldehyde 29, isatoic anhydride 100a, and ammonium acetate. After the addition of ChCl/Asc (70 mol%), the resulting mixture was stirred at 80 °C for 20–65 min, giving a total of nine 2,3-dihydroquinazolin-4(1H)-ones 44 in 76–94% yield ([Scheme 51], Eq. B). After the removal of product by filtration from an aqueous mixture, the NaDESs could be recycled and reused up to five times without loss of efficiency.

Scheme 51 Synthesis of dihydroquinazolin-4(1H)-ones 44 in ChCl/Asc.

In 2022, Zuo, Zheng, and coworkers[86] developed the synthesis of hydroxy methyl furfural (HMF) 49b from glucose 48b, starches, and starchy food waste. The authors used α-Al₂O₃ or Al(OH)₃ as catalysts, NaDESs as solvents, and methyl isobutyl ketone (MIBK) as cosolvent, to avoid the formation of by-products ([Scheme 52], Eq. A). The NaDESs used were composed of ChCl, betaine hydrochloride (BHC), water, and glucose 48b. Several tests were conducted to find the best reaction condition, which was encountered using: Al(OH)₃ (0.1 g), 0.1 g of starting material, 0.1 g of BHC, 0.75 g of water, and 0.5 g of ChCl, and 10.0 g MIBK, at 140 °C for 2 h. The product HMF 49b was obtained in 63.6% yield. Instead, when Al₂O₃ (0.1 g) was used as a catalyst, the yield of HMF was 67.1%, using the same conditions but 0.35 g of ChCl instead of 0.5 g. Moreover, the authors conducted a study on the recyclability of the catalysts and the NaDESs, which could be reused in situ six times.

Scheme 52 Synthesis of HMF 49b from different sources using NaDESs as solvent.

Another work on the transformation of carbohydrates in HMF in carbohydrate-derived NaDESs was published in 2023 by Zuo and coworkers ([Scheme 52], Eq. B).[87] They employed a previously prepared multilayer mesoporous carbon as catalyst in 50%, with carbohydrates, such as glucose 48b, fructose 48c, and sucrose 48d (0.9 g), in the presence of ChCl (3.6 g) and CH₃CN as cosolvent. The best results achieved were: from glucose, 60.1% of conversion; from fructose, 91.3%; and from sucrose, 68% at 120 °C after 2 h of reaction. In the case of glucose and sucrose, the best catalyst was sulfonic acid-functionalized mesoporous carbon catalyst (S-PMC), while S-PCM impregnated with CrCl₃·6H₂O was the best one for fructose.

In 2024, Qiao and coworkers[88] reported the dehydration reaction of N-acetyl-d-glucosamine 48e to produce 3-acetamido-5-(1′,2′-dihydroxyethyl)furan (Chromogen III) 49c and 3-acetamido-5-acetylfuran (3A5AF) 49d ([Scheme 53]). After the optimization study, the best reaction condition to prepare Chromogen III 49c was stirring at 130 °C for 2 h in a binary NaDES, composed of proline and glycerol (Pro/Gly), forming the product in 26%. On the other hand, 3A5AF 49d was prepared in 39% in ternary NaDES, composed of proline, glycerol, and lactic acid (Pro/Gly/LA), after 2.5 h at 120 °C. The authors commented that NaDESs, besides acting as solvents, interacted through hydrogen bonds with substrate 48e and species 49c to ensure the success of the reaction.

Scheme 53 Synthesis of Chromogen III 49c and 3A5AF 49d using Pro/Gly and Pro/Gly/LA.

 

MissingLinkText

5

Conclusions and Outlook

Among the diversity of green alternatives already in use, like “on water” and “in water” reactions; solvent-free mechanochemical processes; and the use of perfluorinated liquids, supercritical carbon dioxide, and ionic liquids, bio-based solvents are emerging as the light at the end of the tunnel. As demonstrated in this review, the diversity of small molecules that can be used as solvents in organic synthesis, alone or in mixtures, has increased in recent years. In addition to being renewable, the versatility of bio-based solvents allows their use in a plethora of reactions, from nucleophilic substitutions to multicomponent reactions and metal-catalyzed couplings. In most cases, the solvent can be easily recovered and reused in new reactions, avoiding the necessity of laborious pretreatment or purification; also their NMR trace impurity has been catalogued.[89] However, some bottlenecks have limited the rapid diffusion and massive use of bio-based solvents. One of these is the cost of production, which, of course, should decrease as the scale of production increases, following the example of bioethanol and glycerin, which are produced on a large scale and are, therefore, more economical. Versatile solvents such as GVL and cyrene are likely to become widely used in the medium term. These are examples of aprotic solvents with relatively high boiling points, a characteristic that is highly desirable for most organic transformations.

Additionally, NaDESs are becoming a viable replacement for second-generation ionic liquids. They are safer and less toxic, have an almost unlimited number of combinations, and can be customized according to the desired application.

Future potential and merging trends in bio-based solvents, still uncovered, could involve machine learning to identify new bio-based solvents with optimal properties (polarity, boiling point, biodegradability). More research on upcycling agricultural and industrial waste, as well as switchable solvents for adaptive reaction media, is crucial to increase the use of bio-based solvents in industrial processes.

In summary, the transition to green solvents is a path of no return. In this context, bio-based solvents play an important role as an attractive option for many chemical transformations. Hence, this review study will be helpful for synthetic organic chemists who are seeking to make the chemistry developed in their laboratories more sustainable.

 

MissingLinkText

 

MissingLinkText

Gabriela T. Quadros

Gabriela T. Quadros was born in 2001 in Gramado-RS, Brazil. She received her BS in Industrial Chemistry (2024) at the Federal University of Pelotas (UFPel), Brazil. She is currently pursuing a master’s degree at the Graduate Program in Chemistry at the UFPel under the supervision of Prof. Eder J. Lenardão.

Livia C. Lima Valente

Livia C. Lima Valente was born in 2000 in Pelotas, RS, Brazil. She received her BS degree in Industrial Chemistry in 2024 from the Federal University of Pelotas. Currently, she is pursuing a PhD in chemistry at the same university, under the supervision of Prof. Daniela Hartwig.

Laura Abenante

Laura Abenante was born in 1987 in Perugia, Italy. She received her MSc in Chemistry and Pharmaceutical Technologies from the University of Perugia (2016) and her MSc degree in Chemistry from Federal University of Pelotas (UFPEL, 2018). In 2023, she earned a PhD degree in Chemistry at UFPEL (2023). In 2023, she held a postdoc position at the University of Caxias do Sul under the supervision of Prof. Thiago Barcellos da Silva. She is currently a postdoc at Federal University of Pelotas under the supervision of Professor Eder J. Lenardão.

Thiago Barcellos

Thiago Barcellos has been a chemistry professor at the University of Caxias do Sul, RS, Brazil, since 2015. He is a researcher in the graduate programs in Biotechnology and Engineering and Materials Sciences. His research is centered on the development of eco-friendly processes for catalysis and biomass valorization. He is also interested in analytical methods, such as high-resolution mass spectroscopy and nuclear magnetic resonance, for elucidating reaction mechanisms. He received his BS degree in Chemistry from the Federal University of Pelotas and his MSc degree in Organic Chemistry from the Federal University of Santa Maria, RS, Brazil. In 2011, he received his PhD in Science – Organic Chemistry – from the University of São Paulo, SP, Brazil, and conducted postdoctoral research at the University of Pennsylvania, PA, USA, from 2011 to 2012.

Daniela Hartwig

Daniela Hartwig was born in 1985 in Pelotas-RS, Brazil. She received her graduate degree (2009), master’s degree (2013), and PhD (2017) in organic chemistry from the Federal University of Pelotas (Brazil). In 2018, she obtained a position as a Professor at the Federal University of Pelotas. Her research focuses on structural modifications in essential oils and the development of green procedures for the preparation of heterocycles and organochalcogen compounds.

Eder J. Lenardão

Eder J. Lenardão, FRSC, was born in 1968 in Sabáudia, PR, Brazil. He received his BS from the State University of Londrina and his MSc degree from Federal University of Santa Maria (UFSM), Brazil. In 1997, he earned a PhD degree in organic chemistry at the University of São Paulo. In 2003, he held a postdoc position at UFSM. In 1997, he obtained a position at the Federal University of Pelotas. In 2015–2016, he spent a year as visiting professor at the University of Perugia (Italy), joining Prof. Claudio Santi’s group. His research interest lies in the area of organic and green chemistry.

Contributorsʼ Statement

Data collection: G.T. Quadros, L.C.L. Valente, L. Abenante, T. Barcellos, D. Hartwig; analysis and interpretation of the data: E.J. Lenardão, D. Hartwig, L. Abenante, T. Barcellos; drafting the manuscript: G.T. Quadros, L.C.L. Valente, L. Abenante, D. Hartwig; revision of the manuscript: L. Abenante, T. Barcellos, D. Hartwig, E.J. Lenardao.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

We would like to express our deepest gratitude to all the authors whose valuable contributions form the foundation of this review. Your dedication, expertise, and insightful research have been indispensable in advancing knowledge about green bio-based solvents.

• References

• 1 Pilon L, Day D, Maslen H. et al. Green Chem 2024; 26: 9697
• 2a Global solvents market to reach 32.7 million metric tons by the year 2026. GlobeNewswire: March 29, 2022. Source: https://www.globenewswire.com/news-release/2022/03/29/2411908/0/en/GlobalSolvents-Market-to-Reach-32-7-Million-Metric-Tons-by-the-Year-2026.html (Accessed on: 23 February 2025)
• 2b Solvents Market Size, Share & Industry Analysis, By Product Type (Alcohols, Ketones, Esters, and Others), Application (Paints & Coatings, Printing Inks, Industrial Cleaning, Adhesives, and Others), and Regional Forecast, 2024–2032. Source: https://www.fortunebusinessinsights.com/industrial-solvents-market-102135 (Accessed on: 09 April 2025)
• 3 Slakman BL, West RH. J Phys Org Chem 2019; 32: e3904
• 4 Winterton N. Clean Technol Environ Policy 2021; 23: 2499
• 5 Anastas PT, Warner JC. Green Chemistry: Theory and Practice. New York: Oxford University Press; 1998
• 6 United Nations. Sustainable Development Goals; United Nations, https://sdgs.un.org/goals (Accessed on: 27 February 2025)
• 7 Simon M-O, Li C-J. Chem Soc Rev 2012; 41: 1415
• 8 Butler RN, Coyne AG. Chem Rev 2010; 110: 6302
• 9 Blackmond DG, Armstrong A, Coombe V, Wells A. Angew Chem, Int Ed 2007; 46: 3798
• 10 Varma RS. ACS Sustainable Chem Eng 2016; 4: 5866
• 11 Simon M-O, Li C-J. Chem Soc Rev 2012; 41: 1415
• 12a Poonam, Geetanjali, Singh R. Applications of ionic liquids in organic synthesis. In Applications of Nanotechnology for Green Synthesis. Inamuddin A, Asiri A. eds Nanotechnology in the Life Sciences. Cham: Springer; 2020: 45-67
• 12b Qureshi ZS, Deshmukh KM, Bhanage BM. Clean Technol Environ Policy 2014; 16: 1487
• 13a Heidari S. Haghniaz R. The Potential Use of Supercritical CO₂ as a Sustainable Solvent in Biocatalytic Reactions. In Green Sustainable Process for Chemical and Environmental Engineering and Science. Inamuddin A, Boddula R, Ahamed MI, Asiri AM. eds Elsevier; 2021: 325-343
• 13b Wu T, Han B. Supercritical Carbon Dioxide (CO₂) as Green Solvent. In Green Chemistry and Chemical Engineering. Han B, Wu T. eds. Encyclopedia of Sustainability Science and Technology Series New York, NY: Springer; 2019
• 14a Verma S, Saini K, Maken S. J Mol Liq 2024; 393: 123605
• 14b Smith EL, Abbott AP, Ryder KS. Chem Rev 2014; 114: 11060
• 15a Curran DP. Pure Appl Chem 2000; 72: 1649
• 15b Gladysz JA, Curran DP, Horváth IT. eds Handbook of Fluorous Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA; 2004
• 16a Soni J, Sahiba N, Sethiya A, Agarwal S. J Mol Liq 2020; 315: 113766
• 16b Chen J, Spear SK, Huddleston JG, Rogers RD. Green Chem 2005; 7: 64
• 17a Capello C, Fischer U, Hungerbühler K. Green Chem 2007; 9: 927
• 17b Häckl K, Kunz W. C R Chim 2018; 21: 572
• 18 Wu X-F, Wang F, Yin Z, He L-n. eds Green Solvents in Organic Synthesis. Weinheim: Wiley-VCH GmbH; 2024
• 19 Yi W-B, Gao X, Zhang W. Biorenewable Solvents for Organic Synthesis. Cham, Switzerland; Springer Nature: 2024
• 20 Wittcoff HA, Reuben BG, Plotkin JS. Industrial Organic Chemicals. New York: John Wiley & Sons; 2004: 136
• 21a Nazaré de Oliveira A, Melchiorre M, Farias da Costa AA. et al. Sustainable Chem Pharm 2024; 41: 101656
• 21b Narasimhamurthy KH, Joy MN, Sajith AM. et al. Lett Org Chem 2023; 20: 945
• 21c Ravichandiran P, Gu Y. Glycerol as eco-efficient solvent for organic transformations. In Bio-Based Solvents. Jérôme F, Luque R. eds Chennai, India: John Wiley & Sons Ltd.; 2017
• 21d Nebra N, García-Álvarez J. Molecules 2020; 25: 2015
• 22 Jordan A, Hall JGC, Thorp RL, Sneddon FH. Chem Rev 2022; 122: 6749
• 23 Gundekari S, Karmee KS. Molecules 2024; 29: 242
• 24 Bousfield TW, Pearce KPR, Nyamini SB, Angelis-Dimakis A, Camp JE. Green Chem 2019; 21: 3675
• 25 Tamargo RJI, Rubio PYM, Mohandoss S, Shim J, Lee YR. ChemSusChem 2021; 14: 2133
• 26 Webb DA, Alsudani Z, Xu G, Gao P, Arnold LA. RSC Sustainability 2023; 1: 1522
• 27 Stini N, Gkizis P, Kokotos C. Org Biomol Chem 2023; 21: 351
• 28 Citarella A, Cavinato M, Amenta A. et al. Eur J Org Chem 2024; 27: e202301305
• 29 Tian C, Dhawa U, Struwe J, Ackermann L. Chin J Chem 2019; 37: 552
• 30 Eliasson SHH, Chatterjee A, Occhipinti G, Jensen VR. ACS Sustainable Chem Eng 2019; 7: 4903
• 31 Tabasso S, Gaudino EC, Acciardo E, Manzoli M, Bonelli B, Cravotto G. Front Chem 2020; 8: 253
• 32 Tabasso S, Calcio Gaudino E, Rinaldi L, Ledoux A, Larini P, Cravotto G. N J Chem 2017; 41: 9210
• 33 Tukacs JM, Marton B, Albert E, Tóth I, Mika LT. J Organometall Chem 2020; 923: 121407
• 34 Tóth I, Tukacs JM, Mika LT. ChemCatChem 2023; 15: e20220148
• 35 Xu M, Zhang K, Zhang J. Mendeleev Commun 2022; 32: 397
• 36 Anastasiou I, Velthoven NV, Tomarelli E. et al. ChemSusChem 2020; 13: 2786
• 37 Anastasiou I, Ferlin F, Viteritti O, Santoro S, Vaccaro L. Mol Catal 2021; 513: 1117877
• 38 Ferlin F, Anastasiou I, Carpisassi L, Vaccaro L. Green Chem 2021; 23: 6576
• 39 Valentini F, Erasmo DB, Ciani M, Chen S, Gu Y, Vaccaro L. Green Chem 2024; 26: 4871
• 40 Mu XY, Wang ZJ, Feng B, Xu L, Gao LX, Satheeshkuma R. RSC Adv 2021; 11: 3216
• 41 Wang L, Jiang K, Zhang N, Zhang Z, Asian J. Org Chem 2021; 10: 1671
• 42 Jiang KC, Wang L, Chen Q, He MY, Shen MG, Zhang ZH. Synth Commun 2021; 51: 94
• 43 Qiu B, Shi J, Hu W, Wang Y, Zhang D, Chu H. Energy 2024; 294: 130774
• 44 Singh LS, Kant K, Banerjee S. et al. Polycycl Aromat Compd 2024; 44: 4832
• 45 Faria CA, Oliveira BCK, Monteiro CA, Santos NE, Gusevskaya VE. Catal Today 2020; 344: 24
• 46 Hao W, Xu Z, Zebiao Z, Cai M. J Org Chem 2020; 85: 8522
• 47 Ismael A, Gevorgyan A, Skrydstrup T, Bayer A. Org Process Res Dev 2020; 24: 2665
• 48 Meninno S, Carrat M, Overgaard J, Lattanzi A. Chem – Eur J 2021; 27: 4573
• 49 Uzunlu N, Pongrácz P, Kollár L, Takács A. Molecules 2023; 28: 442
• 50 Su M, Huang X, Lei C, Jin J. Org Lett 2022; 24: 354
• 51 Breitmaier E. Terpenes: Importance, General Structure, and Biosynthesis, v. 1. Weinheim.: Wiley-VCH Verlag GmbH & Co. KGaA; 2006: 1-3
• 52 Mahato N, Sharma K, Koteswararao R, Sinha M, Baral E, Cho MH. Crit Rev Food Sci Nutr 2019; 59: 611
• 53 Eggersdorfer M. Terpenes. Ullmann’s Encyclopedia of Industrial Chemistry, v. 36. Weinheim.: Wiley-VCH Verlag GmbH & Co. KGaA; 2012: 29-45
• 54 Campos JF, Scherrmann M-C, Berteina-Raboin S. Green Chem 2019; 21: 1531
• 55 Campos JF, Berteina-Raboin S. Catalysis 2019; 9: 840
• 56 Campos JF, Berteina-Raboin S. Catal Today 2020; 358: 138
• 57 Campos JF, Pacheco-Benichou A, Fruit C, Besson T, Berteina-Raboin S. Synthesis 2020; 52: 3071
• 58 Campos JF, Ferreira V, Berteina-Raboin S. Catalysts 2021; 11: 222
• 59 Messire G, Adolf C, Raboin-Berteina S. Chem – Eur J 2024; 30: e202402136
• 60 Dave AY, Mishra A, Talukdar M, Begari E. ChemistrySelect 2022; 7: e202200954
• 61 Kundu T, Mitra B, Ghosh P. Synth Commun 2023; 53: 779
• 62 Nagata Y, Takeda R, Suginome M. ACS Cent Sci 2019; 5: 1235
• 63 Liu M-M, Mu X-Y, Yu L-J, Milaneh S, Zhang C, Wang W-L. Synth Commun 2023; 53: 1981
• 64 Xu L, Mu X, Liu M. et al. Chin Chem Lett 2023; 34: 108063
• 65 Ye L, Thompson BC. ACS Macro Lett 2021; 10: 714
• 66 Lei P, Mu Y, Wang Y. et al. ACS Sustainable Chem Eng 2021; 9: 552
• 67 Messire G, Ferreira V, Caillet E, Bodin L, Auville A, Berteina-Raboin S. Molecules 2023; 28: 6924
• 68 Dargo G, Kis D, Gede M, Kumar S, Kupai J, Szekely G. Chem Eng J 2023; 471: 144365
• 69 Abbott PA, Capper G, Davies DL, Rasheed RK, Tambyrajah V. Chem Commun 2003; 70
• 70 Smith EL, Abbott PA, Ryder SK. Chem Rev 2014; 114: 11060
• 71 Brahma S, Gardas RL. History and development of ionic liquids. In Handbook of Ionic Liquids: Fundamentals, Applications, and Sustainability. Singh P, Rajkhowa S, Sen A, Sarma J. eds Straive, Chennai, India: Wiley; 2023
• 72 Choi YH, van Spronsen J, Dai Y. et al. Plant Physiol 2011; 156: 1701
• 73 Dai Y, van Spronsen J, Witkamp G-J, Verpoorte R, Choi YH. Anal Chim Acta 2013; 766: 61
• 74 Chevé-Kools E, Choi YH, Roullier C, Ruprich-Robert G, Grougnet R, Chapeland-Leclerc F, Hollmann R. Green Chem. 2025
• 75 Karadendrou M-A, Kostopoulou I, Kakokefalou V, Tzani A, Detsi A. Catalysts 2022; 12: 249
• 76 Paparella AN, Messa F, Dilauro G, Troisi L, Perrone S, Salomone A. ChemistrySelect 2022; 7: e202203438
• 77 Thiery E, Delaye P-O, Thibonnet J, Boudesocque-Delaye L. Eur J Org Chem 2023; 26: e202300727
• 78 Tabasso S, Moro R, Gaudino EC, Bruschetta C, Cravotto G. ACS Sustainable Chem Eng 2024; 12: 13810
• 79 Khoshdel MA, Mazloumi M, Zabihzadeh M, Shirini F. Polycycl Aromat Compd 2024; 44: 4440
• 80 Zadem A, Cheraiet Z, Chahra B-H. Polycycl Aromat Compd 2024; 44: 5188
• 81 Giofrè SV, Tiecco M, Ferlazzo A. et al. Eur J Org Chem 2021; 2021: 4777
• 82 Lupidi G, Palmieri A, Petrini M. Green Chem 2022; 24: 3629
• 83 Das A, Dey S, Yadav RN. et al. ChemistrySelect 2023; 8: e202204651
• 84 Komar M, Rastija V, Bĕslo D, Molnar M. J Mol Struct 2024; 1304: 137725
• 85 Hosseinzadeh R, Zarei S, Valipour Z, Malek B. Heliyon 2024; 10: e37170
• 86 Zuo M, Wang X, Jia W, Zhu Y, Zeng X, Lin L. Fuel 2022; 326: 125062
• 87 Zuo M, Che W, Jia W, Zhou Z, Zeng X, Lin L. Ind Crops Prod 2023; 194: 116354
• 88 Zhao J, Guo Z, Pedersen CM. et al. J Mol Liq 2024; 413: 126006
• 89 Cseri L, Kumar S, Palchuber P, Szekely G. ACS Sustainable Chem Eng 2023; 11: 5696

Publication History

Received: 28 April 2025

Accepted after revision: 26 June 2025

Accepted Manuscript online:
01 July 2025

Article published online:
06 August 2025